Pharmaceutical composition in ivermectin emulgel for veterinary use as a promoter system and bio-adhesive in antiparasitic treatment, and method for the production thereof

Abstract

The invention relates to a pharmaceutical composition comprising: at least one antiparasitic active ingredient for providing the pharmacological therapeutic effect; an agent having bio-adhesive properties that helps to reduce the motility and reproduction of the parasites, increasing the period of time for which the product remains on the skin of the animals; an agent having permeation- or absorption-promoting properties that contributes to increasing the cutaneous permeability of the active ingredient; a surfactant agent that is absorbed in an oil-water interface, and as a result, the molecules of said surfactant agent form a kind of bridge between the polar phase (water) and the non-polar phase (oil), thereby making the transition between both phases less abrupt; an oil which will form the oily phase of the emulsion, and which will incorporate the active ingredient; and a neutralizing agent.

1 . A pharmaceutical composition comprising: at least an antiparasitic active principle in charge of providing a pharmacological therapeutic effect; an agent with bioadhesive properties helping to reduce motility and reproduction of infesting parasites, increasing the period of time of the product on the skin of animals; an agent with permeation or absorption promoting properties coadjuvant to increase active principle skin permeability; a surface-active agent or surfactant, which is adsorbed in an oil-water interphase, and consequently, the molecules of said surface-active agent form a bridge between the polar phase (water) and the non-polar phase (oil), thereby making less abrupt the transition between both phases; an oil which will form the oily phase of the emulsion and which will incorporate the active principle; and a neutralizing agent which function is to put the system close to neutrality in order to make the formulation applicable, further increasing system viscosity by deprotonizing Carbocol carboxyl groups (COOH) and passing to COO— whereby viscosity is increased and the system becomes more transparent. 
     
     
         2 . The pharmaceutical composition according to  claim 1 , wherein the pharmaceutical composition is present in semisolid or pour on emulgel form, wherein the gel is incorporated in an aqueous phase, while the active principle is incorporated in an oily phase. 
     
     
         3 . The pharmaceutical composition according to  claim 2 , wherein the at least one antiparasitic active principle is ivermectin. 
     
     
         4 . The pharmaceutical composition according to  claim 3 , wherein ivermectin is present in the composition in a concentration range from 0.2 to 1% w/w. 
     
     
         5 . The pharmaceutical composition according to  claim 4 , wherein ivermectin is present in the composition in a concentration of 0.5% w/w. 
     
     
         6 . The pharmaceutical composition according to  claim 1 , wherein the agent with bioadhesive properties is selected from the group comprising: tragacanth gum, guar gum, karaya gum, sodium alginate, gelatin, chitosan; cellulose derivatives such as methylcellulose, sodium carboxymethylcellulose, hydroxyethyl cellulose, hydroxypropylcellulose, polyethylene glycols polyvinyl alcohol, Carbopol 940, acrylic and methacrylic acid polymers and copolymers, polyalkylcyanoacrylates, polycarbophil, or any other substance with bioadhesive properties. 
     
     
         7 . The pharmaceutical composition according to  claim 6 , wherein the agent with bioadhesive properties is Carbopol 940. 
     
     
         8 . The pharmaceutical composition according to  claim 7 , wherein the agent with bioadhesive properties is present in the pharmaceutical composition in a concentration range from 5 to 10% w/w. 
     
     
         9 . The pharmaceutical composition according to  claim 8 , wherein the agent with bioadhesive properties is present in the pharmaceutical composition in a concentration of 8.26% w/w. 
     
     
         10 . The pharmaceutical composition according to  claim 1 , wherein the agent with permeation or absorption promoting properties is selected from surface-active agents or surfactants, organic solvents, unsaturated fatty acids and some organic materials, wherein the more effective promoter agents are non-ionic surfactants, such as sorbitol-derived fatty acids, and more preferably sorbitan laureate or instead, organic solvents having a HLB value Hydrophilic-Lipophilic Balance value) between 6 and 30, which are selected from the group comprising: glycerol ester chemicals, polyglycerol esters, alkyl fatty acid esters, ethoxylated sorbitan esters, alcohol ethoxylates, lanolin ethoxylates, ethoxylated fatty methyl esters and alkanolamides, or any other substance with absorption promoting properties on skin. 
     
     
         11 . The pharmaceutical composition according to  claim 10 , wherein the agent with permeation or absorption promoting properties is Transcutol®. 
     
     
         12 . The pharmaceutical composition according to  claim 11 , wherein the agent with permeation or absorption promoting properties is present in the pharmaceutical composition in a concentration range from 0.05 to 15% v/v. 
     
     
         13 . The pharmaceutical composition according to  claim 12 , wherein the agent with permeation or absorption promoting properties is present in the composition in a concentration of 10% v/v. 
     
     
         14 . The pharmaceutical composition according to  claim 1 , wherein the surface-active agent or surfactant is selected from the group comprising Pluronic F68, Tween® 60, Tween® 80, Span® 60, Span® 80. 
     
     
         15 . The pharmaceutical composition according to  claim 14 , wherein the surface-active agent or surfactant is Pluronic F68. 
     
     
         16 . The pharmaceutical composition according to  claim 15 , wherein the surface-active agent or surfactant is present in the pharmaceutical composition in a concentration range from 0.05 to 15% v/v. 
     
     
         17 . The pharmaceutical composition according to  claim 16 , wherein the surface-active agent or surfactant is present in the pharmaceutical composition in a concentration between 0.1 and 10% v/v. 
     
     
         18 . The pharmaceutical composition according to  claim 1 , wherein the oil is selected from medium chain triglycerides, which are plant-origin fats especially obtained from coconut and palm oil. 
     
     
         19 . The pharmaceutical composition according to  claim 18 , wherein the oil is Captex® Captex 200. 
     
     
         20 . The pharmaceutical composition according to  claim 19 , wherein the oil is present in the composition in a concentration range from 11.2 to 55.5% w/v. 
     
     
         21 . The pharmaceutical composition according to  claim 20 , wherein the oil is present in the composition in a concentration of 27.6% w/v. 
     
     
         22 . The pharmaceutical composition according to  claim 1 , wherein any strong or mild alkali or base is used as neutralizing agent selected from the group comprising sodium hydroxide, potassium hydroxide, ammonium hydroxide, borax, monoethanolamine, diethanolamine, triethanolamine. 
     
     
         23 . The pharmaceutical composition according to  claim 22 , wherein the neutralizing agent is triethanolamine. 
     
     
         24 . The pharmaceutical composition according to  claim 23 , wherein the neutralizing agent is present in the composition in a concentration range from 0.1 to 2.0% v/v. 
     
     
         25 . The pharmaceutical composition according to  claim 24 , wherein the neutralizing agent is present in the composition in a concentration range from 0.1 to 1% v/v. 
     
     
         26 . The use of a pharmaceutical composition comprising ivermectin of  claim 1 , in manufacturing a medicament for treatment of parasitic diseases. 
     
     
         27 . A method of preparation of the pharmaceutical composition of  claim 1 , characterized by comprising the steps of:
 (a) placing an amount in the range from 5 to 10 g of bioadhesive agent in 100 ml de distillate water and moisturizing for 24 hours;   (b) homogenizing with a variable speed stirrer with a serrated propeller in order to form a gel without air;   (c) adding to above gel solution an amount in the range from 50 to 65 ml of glycerin and mixing with a variable speed stirrer with marine propeller until full component homogenization, obtaining a bioadhesive gel preferably at 10%;   (d) weighing a required amount of solution obtained in above step (c), wherein said amount will be in function of the amount of product intended to prepare and adding an amount in the range from 2 to 10 ml of surface-active agent, which must be previously dissolved in a minimum amount of distillate water, heating at a temperature of 45° C. and homogenizing with the variable speed stirrer and marine propeller;   (e) adding slowly and with constant stirring to above mixture, an amount in the range from 3 to 8 ml of permeation promoter agent, keeping stirring and a temperature of 45° C.;   (f) adding to the solution obtained in above step (e) an amount in the range from 0.5 to 2.0 ml, preferably 1.1 ml, del neutralizing agent, preferably triethanolamine, by dropwise addition and constantly stirring to finally obtain the aqueous phase obtaining an opalescent gel.   (g) dissolving an amount in the range from 0.2 to 1 g of active principle in 25 to 30 ml of oil, keeping a temperature of 45° C. and constantly stirring with a magnetic bar until complete dissolution, during a time from 30 to 45 minutes, obtaining the oily phase;   (h) constantly stirring the aqueous phase obtained in steps (a) to (f) and adding slowly the oily phase obtained in step (g) until complete incorporation, wherein both phases must be at a temperature of between 40 and 50° C., and continuing stirring to room temperature.